Particulate matter is associated with different human diseases affecting organs such as the respiratory and cardiovascular systems. Very small particles (nanoparticles) have been shown to be rapidly internalized into the body. Since the sites of internalization and the location of the detected particles are often far apart, a distribution via the blood stream must have occurred. Thus, endothelial cells, which line the inner surface of blood vessels, must have had direct contact with the particles. In this study we tested the effects of metallic nanoparticles (Co and Ni) on oxidative stress and pro-inflammatory response in human endothelial cells in vitro. Exposure to both nanoparticle types led to a concentration-dependent cytotoxic effect. However, the effects on oxidative stress and pro-inflammatory response differed dramatically. Due to the nanoparticle-induced effects, a comparison between metallic nanoparticle- and metal ion-treatment with the corresponding ions was made. Again, divergent effects of nanoparticles compared with the ions were observed, thus indicating differences in the signaling pathways induced by these compounds. These paradoxical responses to different metallic nanoparticles and ions demonstrate the complexity of nanoparticle-induced effects and suggest the need to design new strategies for nanoparticle toxicology.